Pharmacologically active compounds

ABSTRACT

N-Cyano-N&#39;&#39;-heterocyclic-alkylguanidines which are inhibitors of histamine activity.

United States Patent Durant et al.

PHARMACOLOGICALLY ACTIVE COMPOUNDS Inventors: Graham John Durant, Welwyn Garden City; John Colin Emmett, Codicote; Charon Robin Ganellin, Welwyn Garden City, all of England Assignee: Smith Kline & French Laboratories Ltd., Welwyn Garden City, England Filed: Aug. 2, 1973 Appl. No.: 385,027

Foreign Application Priority Data Sept. 5, 1972 United Kingdom 41160/72 Feb. 8, 1973 United Kingdom 6154/73 July 29, 1975 Int. Cl C07d 49/36 Field of Search 260/309, 294.9, 306.8, 260/307, 308, 3l0, 256.4. 250

References Cited UNITED STATES PATENTS 5/1962 Mull 260/294.9 1/1963 Shapiro et al 260/295 Primary ExaminerHarry I. Moatz Attorney, Agent, or FirmJoan S. Keps; Richard D. Foggio; William H. Edgerton [57] ABSTRACT N-Cyano-N-heterocyclic-alkylguanidines which are inhibitors of histamine activity.

6 Claims, No Drawings PHARMACOLOGICALLY ACTIVE COMPOUNDS This invention relates to pharmacologically active compounds, in particular to pharmacologically active N-cyano-N'-heterocyclic alkylguanidines, and pharmaceutical compositions and methods of inhibiting I-I-2 histamine receptors with these compounds. The compounds of the invention can exist as the addition salts, but, for convenience, reference will be made throughout this specification to the parent compounds.

It has long been postulated that many of the physiologically active substances within the animal body, in the course of their activity, combine with certain specific sites known as receptors. Histamine is a compound which is believed to act in such a way but, since the actions of histamine fall into more than one type, it is believed that there is more than one type of histamine receptor. The type of action of histamine which is blocked by drugs commonly called antihistamines (of which mepyramine is a typical example) is believed to involve a receptor which has been designated as I-I-l A further group of substances has recently been described by Black et. al., (Nature 1972, 236, 385) which are distinguished by the fact that they act at histamine receptors other than the H-1 receptor and these other receptors have been designated as H-2 receptors. This latter group of substances, to certain of which the present invention relates, are thus of utility in inhibiting certain actions of histamine which are not inhibited by the abovementioned antihistamines. The substances of this invention may also be of utility as inhibitors of certain actions of gastrin.

Throughout the present specification and claims, by the term lower alkyl we mean an alkyl group containing from 1 to 4 carbon atoms.

The cyanoguanidines with which the present invention is concerned may be represented by the following general formula:

wherein R is hydrogen or lower alkyl such as methyl; n is from 3 to 5; and Het is a nitrogen containing 5 or 6 membered heterocyclic ring such as imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, pyrazole, triazole, thiadiazole, pyrimidine, pyrazine or pyridazine which is optically substituted by lower alkyl, trifluoromethyl, hydroxyl, halogen or amino, or pharmaceutically acceptable acid addition salts thereof.

It will be understood that the structure illustrated in Formula I is only one of several representations and that other tautomeric forms are also covered by the present invention.

In a preferred group of compounds R is methyl. Het is preferably imidazole or thiazole. Particularly useful specific compounds are N-cyano-N'-methyl-N"-[4-(4- imidazolylbutyl)]guanidine, N-cyano-N'-methyl-N"- [3-(4-imidazolylpropyl)]guanidine and N-cyano-N'- methyl-N -[4-( 2-thiazolylbutyl) ]quanidine.

The compounds of the present invention maybe produced from an amine of the formula Het-(CH ),,NH wherein Het and n have the same significance as in Formula I by reaction thereof with an isothiourea or isourea of formulae II:

N-Cll RY-C NHR

Het (CH lll-l C wherein I-let, n and R have the same significance as in Formula I may be reacted with a heavy metal salt of cyanamide such as the lead, mercury or cadmium salt. This process may be conveniently carried out in a solvent such as acetonitrile or dimethylformamide. In a modification of this process the thiourea of Formula II] is first reacted with a desulphurising agent such as a heavy metal salt or oxide and then treated with cyanamide.

An advantageous method for the production of compounds of Formula I is by the reaction of an amine of Formula Het (CI-l ),,NI-l with a cyanodithioimidocan bonate or a cyanoimidocarbonate of Formula IV:

(RY) C N CN FORMULA IV wherein R is alkyl, preferably methyl and Y is sulphur or oxygen, preferably sulphur to give an N- cyanoisothiourea or N-cyanoisourea of Formula V.

Het; (CH NH C compound of Formula IV, which in the preferred case is dimethylcyanodithioimidocarbonate, may be reacted sequentially with I-let(CI-l NH, and R NH, without isolation of the intermediate compound of Formula V. In an alternative method for the production of those compounds of Formula I wherein R is hydrogen, the amine of Formula Het(Cl-l ),,Nl-l may be reacted with a metal salt of dicyanamide of formula MN (CN) wherein M is a metal e.g., an alkali metal such as sodium in an appropriate solvent and in the presence of an equivalent amount of a strong acid.

As stated above, the compounds represented by Formula I have been found to have pharmacological activity in the animal body as antagonists to certain actions of histamine which are not blocked by antihistamines such as mepyramine. For example, they have been found to inhibit selectively the histaminestimulated secretion of gastric acid from the perfused stomachs of rats anaesthetised with urethane at doses of from 2 to 256 micromoles per kilogram intravenously. Similarly, the action of these compounds may, in many cases, be demonstrated by their antagonism to the effects of histamine on other tissues which, according to the above-mentioned paper of Black et. al., are H2 receptors.

Examples of such tissues are perfused isolated guinea-pig heart, isolated guinea-pig right atrium and isolated rat uterus. The compounds of the invention have also been found to inhibit the secretion of gastric acid stimulated by pentagastrin or by food. In addition to the above the compounds of the invention also show some anti-inflammatory activity in conventional tests.

The level of activity found for the compounds of the present invention is illustrated by the effective dose range in the anaesthetised rat, as mentioned above, of from 2 to 256 micromoles per kilogram, given intravenously. Many of the compounds of the present invention produce a 50% inhibition in this test at a dose of from 3 micromoles per'kilogram.

Pharmaceutical compositions comprising a pharmaceutical carrier and a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof and methods of inhibiting 1-1-2 histamine receptors which comprise administering to an animal a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof are also objects of this invention.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form ofa troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about mg. to about 1 gm. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the composition in an effective amount to inhibit histamine activity.

The route of administration may be orally or parenterally.

Preferably, each dosage unit will contain the active ingredient in an amount of from about 50 mg. to about 250 mg., most preferably from about mg. to about 200 mg.

The active ingredient will preferably be administered in equal closes one to three times per day. The daily dosage regimen will preferably be from about mg. to about 750 mg., most preferably from about 300 mg, to about 600 mg.

For therapeutic use, the pharmacologically active compounds of the present invention will normally be administered as a pharmaceutical composition comprising as the or an essential active ingredient at least one such compound in the basic form or in the form of an addition salt with a pharmaceutically acceptable acid and in association with a pharmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric, picric and maleic acids.

Other pharmacologically active compounds may in certain cases be included in the composition. Advantageously the compositions will be made up in a dosage unit form appropriate to the desired mode of administration, for example as a tablet, capsule, injectable solution or as a cream for topical administration.

The invention is illustrated but in no way limited by the following examples:

EXAMPLE 1 (Found: C, 54.2; Requires: C, 54.5,

ID IG G EXAMPLE 2 N-Cyano-N'-methyl-N-(3-(4- imidazolyl )propyl)guanidine The reaction of N-methyl-N-(3-(4-imidazolyl propyl)thiourea (7.0 g.) with lead cyanamide (21.8 g.)

under conditions similar to those described in Example 1 afforded N-cyano-N'-methyl-N"-(3-(4-imidazolyl) propyl)guanidine (l.5 g. m.p. l55l56) following chromatography on silica gel with ethyl acetateisopropyl alcohol (2:1) as eluant and recrystallisation from water.

(Found: C,

52.0; H, 6.7; N, 40.8. C H N, requires: C, 52.4; H, 6.8; N, 40.8).

etate to yield N-cyano-N-methyl-N"-[4-(2- thiazolyl)butyl]guanidine m.p. 87-89.5.

(Found: C, 50.7; H, 6.5; N, 29.8; S, 13.5. C H N S requires: C, 50.6; H, 6.4; N, 29.5; S. 13.5)

EXAMPLE 4 Reaction of the following amines:

a. 3-bromo-2-(4-aminobutyl)pyridine b. 3-(4-aminobuty])isothiazole c. 2-(4-aminobutyl)oxazole 3-(4-aminobutyl)isoxazole 3-(4-aminobutyl)pyrazole 3-(4-aminobutyl)- l ,2,4-triazole S-amino-2-( 4-aminobutyl)-l ,3 ,4-thiadiazole 2-(4-aminobutyl)pyrimidine 2-(4-aminobutyl)pyrazine 3-(4-aminobutyl)pyridazine k. 4-methyl-S-(4-aminobutyl)imidazole l. 3-hydroxyl-2-(4-aminobutyl)pyridine m. 4-trifluoromethyl-5-(4-aminobutyl)imidazole n. 4-(5-aminopentyl)imidazole with dimethylcyanodithioimidocarbonate at room temperature overnight in ethanol followed by addition to the reaction mixture of ethanolic methylamine yielded respectively the following products.

a. N cyano-N'-methyl-N"-[4-(3-bromo-2- pyridyl )butyl] guanidine b. N-cyano-N'-methyl-N"-[4-(3-isothiazolyl)butyl]- guanidine. c. N-cyano-N-methyl-N"-[4-(2- oxazolyl)butyl]guanidine. d. N-cyano-N -methyl-N' -[4-( 3-isoxazolyl)butyl ]guandine.

g. h. i. j.

e. N-cyano-N -methyl-N"-[4-( 3- pyrazolyl)butyl]guanidine.

f. N-cyano N-methyl-N"-[4-(3-l ,2,4-

triazolyl)butylJguanidine.

thiadiazolyl )butyl guanidine h. N-cyano-N-methyl-N"-[4-( 2- pyrimidyl)butyl]guanidine.

i. N-cyano-N-methyl-N"-[4-( 2- pyrazinyl)butyl]guanidine.

j. N-cyano-N'-methyl-N-[4-( 3- pyridazyl)butyl]guanidine 6 imidazolyl )butyl ]guanidine. l. N-cyano-N'-methyl-N"-[4-(3-hydroxyl-2- pyridyl)butyl]guanidine. m. N-cyano-N-methyl-N"-[4-(4-trifluoromethyll5- imidazolyl)butyl]guanidine.

n. N-cyano-N-methyl-N"-[5-(4-imidazolyl)pentyl]- guanidine.

EXAMPLE 5 10 Reaction of the amines set out in Example 4 with dimethylcyanodithioimidocarbonate at room temperature overnight in ethanol followed by addition to the reaction mixture of butylamine, ethylamine or of ammonia resulted respectively in the corresponding compounds of Formula I wherein R is butyl, ethyl or hydrogen.

EXAMPLE 6 INGREDIENTS AMOUNTS N-cyano-N'-methyl-N"-[4-(4- imidazolybutyl ]guanidine Sucrose Starch Talc Stearic Acid 150 mg. 75 mg. mg.

Het(CH NH-C NHR wherein R is hydrogen or lower alkyl; n is from 3 to 5; and Het is an unsaturated heterocyclic nucleus selected from imidazole, thiazole, isothiazole, oxazole, isoxazole, pyrazole, triazole, thiadiazole, pyrimidine, pyrazine and pyridazine which nucleus is attached through a carbon atom in said nucleus adjacent to a nitrogen atom and is unsubstituted or monosubstituted by lower alkyl, trifluoromethyl, hydroxyl, halogen or amino, or a pharmaceutically acceptable acid addition salt thereof.

2. A compound of claim 1 wherein R is methyl.

3. A compound of claim 1 wherein Het is imidazole or thiazole attached through a carbon atom in said nucleus adjacent to a nitrogen atom.

4. A compound of claim 1, said compound being N- cyano-N-methyl-N"-[4-(4- imidazolylbutyl 1 guanidine.

5. A compound of claim 1, said compound being N- cyano-N-methyl-N"-[3-(4- imidazolylpropyl)lguanidine.

6. A compound of claim 1, said compound being N- 60 cyano-N'-methyl-N"-[4,-(2-thiazolylbutyl)]guanidine.

rrNr'rrcr) s'rA'rrcs rwrrcNT OFFICE (IERIIFICA'IE) ()F CORRECTION IAt'tNt N(). 3,897,444

BMW 1 July 29, 1975 tNVtNTORtS) Graham John Durant, John Colin Emmett and 4 I Charon Robin Ganellin tt rs ccrtrtrert that error appears rrt the ah0ve---rrterrt|tred patent and that salt! Letters Patent are hereby corrected as shown below:

Column 1, line 46, below the structural formula, insert FORMULA I Column 1, line 65, "quanidine should read guanidine Column 6, line 4, "4-triflu0romethyll5" should read r-trifluoromethyl-S- Signed and Sealed-this eleventh D 3*) Of November 1975 [SEAL I A nest:

RUTH C. MASON M'A'RSHALL DANN :I HKIH K jlir'r'r 7 ('unrnlr'xxlmu'r u! IrIIt'II/S LUIL/ l'rurlvmurks Column 6, line 4, "4trifluoromethyll5" should read UNITED S'IA'IES PA'IICNT oFFrcE (IERII FICATE F CORRECTION IATLNI NU. 3,897,444

BMW 1 July 29, 1975 mvmrorus) Graham John Durant, John Colin Emmett and Charon Robin Ganellin It rs curtrtlert that error appears rn the fll)0V--lt|0tttlftd patent and that Sltltl Letters Patent zuc hereby corrected as shown tretow:

Column 1, line 46, below the structural formula, insert FORMULA I Column 1, line 65, "quanidine" should read guan idine r-trifluoromethyl-S- Signed and Bealcdthis eleventh D a y OF November 1 0 75 lSEAL Allesl: 

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1 wherein R is methyl.
 3. A compound of claim 1 wherein Het is imidazole or thiazole attached through a carbon atom in said nucleus adjacent to a nitrogen atom.
 4. A compound of claim 1, said compound being N-cyano-N''-methyl-N''''-(4-(4-imidazolylbutyl))guanidine.
 5. A compound of claim 1, said compound being N-cyano-N''-methyl-N''''-(3-(4-imidazolylpropyl))guanidine.
 6. A compound of claim 1, said compound being N-cyano-N''-methyl-N''''-(4-(2-thiazolylbutyl))guanidine. 